This invention relates to a biocompatible composition suitable for vitreous replacement or substitute as well as methods of treating disorders of the eye with vitreous replacement or substitute.
Clinically vitreous replacement in ophthalmology has been an important goal for clinicians for over half a century. Vitreous, the jelly-like substance which fills three-fourths of the eye, is a clear transparent material, comprised of 99% water. The vitreous provides shape to the eye, transmits light, and forms a semi-solid support for the retina against the choroid. When the vitreous is physically altered or becomes opaque as a result of hemorrhage, permanent blindness can result. For example, should the vitreous partially liquify, which often occurs with age, disease or other factors, its supporting capability is diminished and retinal detachment may ensue as a result of pulling of the retina. Furthermore, the vitreous may become opaque due to cellular infiltration or hemorrhage. Cellular infiltration is common in a number of inflammatory processes of tissue surrounding the vitreous. As a consequence of inflammation, opacification and degeneration of the vitreous occurs. Vitreous hemorrhage is also common, particularly in diabetecs. This occurs when the normal and abnormal retinal vessels rupture hence bleeding into the vitreous, which then develop into large opaque areas. Unlike most other tissue, vitreous is avascular and does not contain a significant number of scavenging macrophages. Therefore, if foreign agents or blood penetrate the vitreous, they may permanently remain in the vitreous, thereby leading to partial or total vision impairment.
Biochemically, the rigidity and viscosity of the vitreous is the result of a delicate fibril meshwork of collagen-like protein, intertwined with hyaluronic acid. Hyaluronic acid, which is responsible for the viscosity of the vitreous, is a mucopolysacharide. Its function is to keep the vitreous from separating into solid and liquid components, thus preventing the collagen from collapsing. The soluble components include glycoproteins, glucose, sodium, potassium, bicarbonate and calcium.
Vitreous replacement has been attempted over the last twenty years, mainly for the two reasons. First is the vitreous opacification produced as a result of aging, trauma, inflammation and hemorrhage. Second is the vitreous degeneration which causes traction on the retina with subsequent retinal detachment. Although such vitreous replacement with animal and human vitreous has been attempted, it has been proven not to be useful compared to other easily available substitutes which, because of their properties, could exert tamponading effects on the retina, or be simply replaced by body fluid.
Among the vitreous replacements currently used are various infusion fluids, generally applied during surgical procedure to remove the vitreous opacities (a procedure called vitrectomy). Previous investigations have demonstrated that physiologic saline solution, containing glucose, bicarbonate, potassium, and calcium is sufficient to maintain the transparency of the media and not be toxic to the lens and the cornea. A review of these substances can be found in publications by: 1) McEnerney JK and Peyman GA, Simplification of glutathione-bicarbonate-Ringer solution: Its effect on corneal thickness, Investigative Ophthalmology & Visual Science 1977, 16(7):657-660, and 2) Benson WE et al, Intraocular irrigating solution for pars plana vitrectomy: Prospective randomized double blind study, Archives of Ophthalmology 1981; 99:1013. The infusion fluids are generally used to replace the vitreous that has been opacified by hemorrhage or inflammation. Since these fluid substitutes do not exert any significant tamponading effect on the retina because of their liquidity properties, they do not provide support to the retinal structure. Furthermore, these substitutes are replaced by body fluid, generally less than one day after application.
A second application of the vitreous substitutes has been for treatment of retinal detachment. Vitreous replacement has been investigated extensively by surgery. The general technique has been the injection of replacement material, combined with prior or simultaneous drainage of the vitreous or subretinal fluid. Although irrigating solutions have been used to increase the intraocular pressure in these conditions, the solutions do not provide any tamponading effects, as mentioned previously.
However, intraocular gases have proved to be useful in vitreous and retinal detachment surgery. Postoperative hypotony (reduced intraocular pressure) and choroidal effusion can be prevented by restoring intraocular volume. Certain gases can tamponade retinal tears until a permanent chorioretinal adhesion forms to seal the retinal tear. Gases, however, have been found to have certain disadvantages, largely because of their expansion property after injection into the vitreous cavity. They can raise the intraocular pressure, causing the occlusion of central retinal artery. Furthermore, postoperative prone positioning is of importance to prevent pupillary block glaucoma. Contact of the gas with the lens can induce cataract formation, while contact between gas and corneal endothelium can cause corneal opacification. Among the gases used for vitreous substitutes are air, oxygen, nitrogen, carbon dioxide, argon, and other inert gases. The disadvantage of these gases is rapid reabsorption from the vitreous cavity, generally within one or two days. Thus its purpose as a supporting element is considerably reduced following reabsorption for the vitreous. Because of this, other gases have been explored which could expand and remain in the eye longer than air when injected in a small volume. Among these gases that have been investigated as possible temporary vitreous substitutes are sulfur hexafluoride (SF.sub.6), octofluorocyclobutane (C.sub.4 F.sub.8) and other perfluorocarbon gases. For a review, see publications by: 1) Vygantas CM, Peyman GA et al, Octafluorocyclobutane and other gases for vitreous replacement, Archives of Ophthalmology 1973; 90:235-2, 2) Taneu HL, Gas injection in the rabbit vitreous: A prelimary study, Canadian Journal of Ophthalmology 10972, 7:349, 3) Lincoff H et al, The perfluorocarbon gases in the treatment of retinal detachment, Ophthalmology 1983, 90:546-551. These substances are very useful in tamponading the retina for 7-30 days in the postoperative period, after which the gas is generally absorbed by the body fluid. After the absorption of the gas, the tamponading effect and volume expanding effect completely disappears. After this the eye must depend on its own natural mechanisms for production of intraocular fluid. Complications associated with the use of these gases include gas expansion, increased intraocular pressure, glaucoma and occlusion of central retinal artery.
Another chemical substance used for vitreous replacement is hyaluronic acid, which is naturally found in the vitreous humor cavity. Hyaluronic acid does not provide any tamponading effect on the retina during surgery or afterwards, partly because of its low surface tension and its specific gravity. It is generally absorbed into the body within 14 days after application. See Balaz EA et al, Hyaluronic acid in the replacement of vitreous and aqueous humor, Modern Problems in Ophthalmology 1972, 10:390. Thus in order to provide a clear vitreous substitute without volume expansion and absorption, investigators have evaluated other classes of material which could be injected into the eye. These include silicones, fluorosilicones and perfluorocarbon liquids.
Silicones are polymers of alternating silicon and oxygen atoms where the silicon atom has various organic groups attached. Polymethylsiloxanes are optically clear. Their specific gravity is less than 1 (0.9), and the viscosities of various preparations can be synthesized so as to vary between 0.65 and 60,000 cs. In ophthalmology, viscosities between 10 and 12,500 cs have been used to maintain the clarity of the vitreous and to reposition the retina. The initial work was done by Stone in 1958 (Stone W Jr. Oculoplasty in surgery of the eye. New England J of Medicine 1958; 258:486) and later in humans (Cibis Pa. Recent method in the surgical treatment of retinal detachment: Intravitreal procedures, Transactions of the Ophthalmological Societies of the United Kingdom 1965, 85:111. Subsequently, numerous investigators have used silicone oils with viscosities of 1000 to 12,500 cs for vitreous replacement. Because of its visco-liquidity property, silicone oil can move in the postoperative period and come in contact with the lens, causing cataract, or, in aphakic patients may contact the corneal endothelial cells, causing corneal endothelial damage. Furthermore, the silicones can emulsify in the postoperative period and migrate from the vitreous cavity into the anterior chamber and restrict or close the outflow channels for intraocular fluid. In addition, emulsified silicone oil is not optically transparent. Therefore, investigators have removed the silicone after implantation, generally between one to six months. After removal of silicone, and its replacement with physiologic saline solution or air, the body has to replace this material, again depending on its own natural regenerating power to maintain the intraocular pressure and provide intraocular support for the retina.
For a review of vitreous replacement with silicone, reference again is made to the publications by Leaver PK et al, Silicone oil injection in the treatment of massive preretinal retraction: II. Late complications in 93 eyes, British Journal of Ophthalmology 1979, 63:361-367, and Peyman GA et al, Randomized clinical trial of intraocular silicone vs. gas in the management of complicated retinal detachment and vitreous hemorrhage, International Ophthalmology 1987, 10:221-234.
Other group of synthetic materials includes perfluorocarbon liquids. Perfluorocarbon liquids were initially developed as a blood substitute. The initial studies evaluating their use as vitreous substitute was performed by Haidt et al and has been extensively reported in Clark's U.S. Pat. No. 4,490,351. Because of the high specific gravity, perfluorocarbon liquids can exert a tamponading effect on the retina when injected into the eye. Of all perfluorocarbon liquids studied thus far, only perfluorophenanthrene has been left inside the eye for a period of up to six months without causing toxic reaction to the retina and the lens. However, if perfluorocarbon liquids come in contact with the corneal endothelial cells, they can damage corneal endothelial cells within 2-3 weeks. Therefore, it should be used only in phakic eyes. In general, perfluorocarbon liquids can also emulsify between 3-6 months. However, the emulsification of perfluorocarbon liquid, although it creates a haze, is not as severe as emulsificaion of silicone. Perfluorocarbon liquids are used either during surgery (as a tool to reattach the retina) and removed immediately following surgery, or are used as temporary vitreous substitute, generally for a period of one month, to provide a tamponading effect on the retina until scar formation is achieved. Perfluorocarbons have to be eventually replaced either with physiologic saline or air, and after replacement again, the eye has to depend on its own by producing intraocular fluid to provide support for the retina.
Another synthetic material used for vitreous replacement is acrylamide gel which has been reported by Muller, Jensen K, Oculoplastic vitreous replacement with acrylamide: A preliminary report, Modern Problems of Ophthalmology 1974, 12:385. The use of this substance has been similar to the use of silicone in the vitreous cavity. It has been injected in small volumes to provide some support during and after surgery for retinal detachment.
As mentioned previously, all the currently available vitreous substitutes have been developed to provide a temporary support for the retina, either during surgery or in the immediate postoperative period. They are generally liquid in nature, which can diffuse from the vitreous cavity into the anterior chamber, and can cause corneal damage and opacification when they come in contact with the corneal endothelium cells. Furthermore, after their removal, which becomes imperative because of the emulsification and migration, hypotony occurs. Hypotony often is a common complication after vitrectomey, specifically after traumatic eye injuries or related reoperation for retinal detachment. Eyes with either preexisting hypotony, severe trauma, prolonged surgical procedure or preoperative inflammation, appear more susceptible to development of chronic hypotony after a vitrectomy. Medical treatment of hypotony includes the use of topical steroids to decrease any associated intraocular inflammation. Surgical methods to treat hypotony include application of diathermy over the possible cyclodialysis cleft to block the exit of intraocular fluid and prevent rapid flow of intraocular fluid toward the choroid.
Temporary use of the hyaluronic acid maintains the intraocular pressure for a period of two weeks, while certain gases can maintain the intraocular pressure for a month. However, after their absorption, the eye becomes hypotonic with subsequent shrinking of the globe and collapse of the sclera. Generally, this complication is accompanied by exudative detachment of the retina and, with time, the retina disorganizes. Because of loss of corneal clarity, the vision is completely lost.